Abstract
Pregnane X receptor (PXR, NR1I2) is a member of the ligand-activated nuclear receptor superfamily. This receptor is promiscuous in its activation profile and is responsive to a broad array of both endobiotic and xenobiotic ligands. PXR is involved in pivotal cellular detoxification processes to include the regulation of genes that encode key drug-metabolizing cytochrome-P450 enzymes, oxidative stress response, as well as enzymes that drive steroid and bile acid metabolism. While PXR clearly has important regulatory roles in the liver and gastrointestinal tract, this nuclear receptor also has biological functions in breast tissue. In this review, we highlight current knowledge of PXR’s role in mammary tumor carcinogenesis. The elevated level of PXR expression in cancerous breast tissue suggests a likely interface between aberrant cell division and xeno-protection in cancer cells. Moreover, PXR itself exerts positive effect on the cell cycle, thereby predisposing tumor cells to unchecked proliferation. Activation of PXR also plays a key role in regulating apoptosis, as well as in acquired resistance to chemotherapeutic agents. The repressive role of PXR in regulating inflammatory mediators along with the existence of genetic polymorphisms within the sequence of the PXR gene may predispose individuals to developing breast cancer. Further investigations into the role that PXR plays in driving tumorigenesis are needed.
Highlights
Pregnane receptor (PXR) (NR1I2), termed steroid and xenobiotic receptor (SXR) in humans, is a nuclear receptor that acts as a xenobiotic and endobiotic sensor that recognizes a large variety of hydrophobic ligands [1]
First discovered in 1998, PXR is a key regulator of the expression of cytochrome-P 450 (CYP) enzymes, including CYP3A4 and CYP2B6 [4,5,6,7,8], which metabolize a variety of toxins, carcinogens, and clinically relevant chemotherapeutic agents [1,9,10,11,12,13]
The role of PXR as a nuclear receptor has evolved to include regulation of families of genes involved in oxidative stress, steroid and bile acid metabolism, inflammation, apoptosis, cell proliferation, and cell cycle maintenance [14,15,16,17,18]
Summary
Pregnane receptor (PXR) (NR1I2), termed steroid and xenobiotic receptor (SXR) in humans, is a nuclear receptor that acts as a xenobiotic and endobiotic sensor that recognizes a large variety of hydrophobic ligands [1]. The role of PXR as a nuclear receptor has evolved to include regulation of families of genes involved in oxidative stress, steroid and bile acid metabolism, inflammation, apoptosis, cell proliferation, and cell cycle maintenance [14,15,16,17,18]. Multi-drug resistance-associated protein 2 (MRP2) and MRP3, both of which are responsible for efflux on conjugated substrates into bile or blood, respectively, are proteins encoded by PXR-target genes [22,23,24]. Because PXR is important for the uptake and efflux of steroid hormones and metabolites due to the variety of transport proteins that are encoded by PXR-target genes, its ability to link endocrinology, pharmacology, and cancer biology is essential to maintaining cellular homeostasis. PXR is involved in metabolism of estrogen and estrogen metabolites, in addition to chemotherapeutic drugs making it a potential therapeutic target
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